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The Structure and Activity of Selegiline, its
Figure 1: Selegiline (l-deprenyl), N-propargyl levo-methamphetamine
Organic chemistry is for people who like to cook!
Selegiline, or l-deprenyl, was first synthesized in 1962 by Joseph Knoll. It is a
very close derivative of l-methamphetamine identical but for the addition of a
propargyl group to its single nitrogen atom. l-Methamphetamine is itself one of the
many derivatives of phenethylamine the foundation for a great number of com-
pounds of psychopharmacological interest While selegiline does inherit some
of the pharmacological actions characteristic of phenethylamines, the addition of
the rather innocuous-looking propargylamine group compounds and complements
those with its own, truly surprising, dimension of activity.Pharmacological Activity of Propargylamines
The monoamine oxidase enzymes, types A and B, are the body’s primary means
of deactivating amines, or compounds derived from ammonia by replacing one
or more of its hydrogen atoms with hydrocarbon groups. Though both enzymes
catalyse the oxidation reaction with amines resulting in the production of ammo-
nia and hydrogen peroxide shown in equation they may be characterized by the
compounds (or “substrates”) they work on, as well as by the compounds which
inhibit their activity. While MAO-A preferentially deaminates serotonin and nora-
drenaline and is selectively inhibited by clorgyline, MAO-B tends to catalyse the
reduction of dopamine and β-phenethylamine and may be inhibited by aliphatic
RCH2NH2 + H2O + O2 −→ RCHO + NH3 + H2O2
As a selective and irreversible inhibitor of MAO-B, selegiline prevents the
deamination of dopamine and β-phenethylamine, thus increasing the concentra-
tion of those monoamines while restricting the production of hydrogen peroxide,
a pro-oxidant or “reactive oxygen species” (ROS). By increasing dopamine lev-
els, selegiline forestalls and decreases by 30–40% the need for levodopa therapy in
cases of Parkinson’s Disease, a condition marked by severe dopamine deficiencies.
The increase in phenethylamine caused by selegiline may also contribute to its ther-
apeutic value for Parkinson’s, as it is known to promote the release of dopamine
and inhibit its transport. Although most valuable as an adjunct to levodopa therapy,
selegiline is somewhat effective as a monotherapy, improving scores on the Unified
Parkinson’s Disease Rating Scale by 5–30%.
The “Free Radical Theory of Aging” hypothesizes that the rate at which one
ages is proportional to the ratio of pro- to anti-oxidants. When the balance is tipped
towards pro-oxidants, ROS are more free to cause oxidative damage, hastening the
aging process. Selegiline is thought to tip the balance in the other direction in
part, at least, by inhibiting the metabolism of monoamines by MAO-B and thereby
diminishing the production of hydrogen peroxide. This action may seem even more
significant in light of reports that MAO-B levels begin increasing with age around
50–60, is more active in Alzheimer’s and Parkinson’s patients, and is found in high
Selegiline has, additionally, been demonstrated to protect against the oxidative
damage to serotonin terminals caused by large doses (40 mg/kg) of MDMA
This could be explained by selegiline’s inhibition of MAO-B: by interfering with
the deamination of the large amount of dopamine released by MDMA, it would
also inhibit the production of the ROS thought to cause the damage It seems
just as likely, however, that this damage could be prevented by the antioxidant
The propargyl group also appear to protect against neurodegeneration by pre-
venting apoptosis, or programmed cell death. Marumaya et al have proposed that
selegiline and related compounds bond to a protein with a tertiary structure very
Figure 6: Rasagiline, N-propargyl-1-(R)aminoindan
similar to that of MAO-B, triggering “the cellular process to repress the apoptotic
Superoxide dismutase (SOD) and catalase are antioxidant enzymes (AOEs)
which work to prevent oxidative damage to the body and brain by reactive oxygen
species (ROS). Though Knoll initially found that selegiline increased the activity
of AOEs, his subsequent research with a different strain of rat failed to corroborate
this result. Further work by Kitani et al has done much to elucidate the relationship
of selegiline to AOEs, concluding that the dose-effect graph follows an inverse U
shape, increasing to a certain, optimal dose and declining steadily thereafter
As an aside, the response of AOEs to selegiline is paralleled by that of the
lifespan of various animals (mice, rats, hamsters, and beagles) to the same. Both
dose-effect graphs follow an inverted U shape, and Kitani et al maintain this as the
primary support for their working hypothesis that the upregulation of AOEs and
extension of lifespan observed with selegiline treatment are causally connected.
This optimal dose is heaviliy dependent on the activity of the hepatic microso-
mal cytochrome P-450 enzyme responsible for the metabolism of selegiline, which
itself is dependent not only on the age, sex, and genetic strain of the organism, but
also on the length of time over which selegiline is administered. The difficulty of
extrapolating these results to humans is illustrated by studies in which Kitani ad-
ministered various doses of selegiline to our closer relatives, beagles and monkeys:
while a dose of 0.17 mg/kg, “roughly” equivalent to that prescribed for Parkinson’s
Disease (10 mg/day), was most effective for young male monkeys, a much larger
dose of 1.0 mg/kg gave the best results for female beagles.
Other propargylamines share in selegiline’s effect on AOEs, albeit with vary-
ing degrees of potency. Of those listed by Kitani et al, selegiline is the most ef-
fective, followed by rasagiline R-2HMP and R-2HP. Though the relation
of the larger structures of these molecules to their effects on SOD and catalase is
largely unknown, Kitani does expect that selegiline should be more potent than
desmethylselegiline, given that R-2HMP is more potent than its desmethyl deriva-
Catecholamine Activity Enhancement
Like many derivatives of phenethylamine, selegiline stimulates the activity of the
sympathetic system of the brain. As a catecholamine activity enhancer (CAE),
selegiline intensifies the response of catecholaminergic neurons by increasing the
impulse-mediated release of catecholamines. It is unique, however, in that it does
not displace catecholamines from their stores, which property tends to lead to de-
pendence, as exemplified by dextro-methamphetamine
In a fascinating article entitled “Sex, Performance, and Longevity,” Knoll es-
tablishes an apparently solid, heretofore unknown, link between sexual activity,
learning ability, and lifespan in rats via “a hitherto unknown brain mechanism that
controls general activity and thereby, indirectly, the duration of life.”
Knoll first shows that the lifespan of normal, placebo treated rats is proportional
to their sexual activity and learning performance: rats predetermined to have “low”
sexual and learning performance as measured by standard tests lived about 134
weeks, while those which scored as “high” performers lived about 151 weeks, or
Finally, he reports that maintaining rats with a daily, 0.25 mg/kg dose of se-
legiline until death lengthened lifespan and increased scores in tests of sexual
and learning performance: selegiline-treated, low-performing rats lived about 152
weeks, or 13% longer than their untreated peers, and selegiline-treated, high-performing
rats lived about 185 weeks, or 22% longer.
At each step, increases in lifespan are linked with increases in sexual perfor-
mance, and each of these is tied to learning ability. Moreover, life-long mainte-
nance of rats on selegiline is shown to increase all three as compared to placebo-
treated peers; initially low-performing rats treated with selegiline outlive their un-
treated, high-performing peers by roughly a month, improve in measures of sexual
and learning performance, and maintain their ability to perform beyond that of their
Pharmacokinetics
Selegiline is administered therapeutically at a dose of 5-10 mg. It is taken up
by the body quickly, and reaches its peak concentration in the plasma within 30–
120 minutes. MAO-B is irreversibly inhibited by 90% within 30–90 minutes, and
remains so until it can be re-synthesized by the body – a period of up to 40 days.
Selegiline is primarily metabolized in the liver by the cytochrome P450 en-
zyme into desmethylselegiline l-methamphetamine and l-amphetamine
These compounds are further metabolized by ring hydroxylation into p-hydroxy-
amphetamine p-hydroxymethamphetamine, and p-hydroxy-N-propargylam-
phetamine, or by β-carbon hydroxylation into ephedrine norephedrine, pseudo-
Though selegiline is typically taken orally, transdermal administration may, in
some ways, be favorable. When first-pass metabolism in the liver is circumvented,
the maximum plasma concentration of selegiline is increased 60-fold, and the bal-
ance of metabolites is altered significantly, halving the production of (levo) am-
phetamines while increasing levels of desmethylselegiline, which is itself a propar-
Figure 7: Nordeprenyl, Desmethylselegiline
Composed primarily of a phenethylamine base and a propargylamine group,
selegiline inherits characteristics of both. From phenethylamine, selegiline de-
rives its ability to enhance catecholamine activity, multiplying the response of cat-
echolaminergic nerves. From propargylamine, selegiline inherits its ability to in-
hibit monoamine oxidase B, prevent apoptosis, protect against oxidative damage
caused by the deamination of monoamines, and increase the activity of antioxidant
Figure 12: MDMA (Ecstasy), 3,4-methylenedioxymethamphetamine
Figure 13: Dopamine, 3,4-dihydroxyphenylethylamine
Figure 16: MDPL, 3,4-methylenedioxy-N-propargylamphetamine
Figure 17: Synthesis of l-deprenyl from phenylalanine
enzymes. With the combination of these groups, selegiline exhibits more novel
properties, including CAE without catecholamine release, and offers a unique and
unlikely combination of mechanisms which work to make it a valuable treatment
for Parkinson’s Disease. Last, but not least, is evidence that it can actually extend
lifespan and preserve sexual and learning performance.References
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